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【结 构 式】 
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【分子编号】32107 【品名】5-methyl-3-isoxazolecarbonyl chloride 【CA登记号】 |
【 分 子 式 】C5H4ClNO2 【 分 子 量 】145.545 【元素组成】C 41.26% H 2.77% Cl 24.36% N 9.62% O 21.99% |
合成路线1
该中间体在本合成路线中的序号：(XXVIII)Final coupling: Deprotection of (XXVI) with HCl in dioxane followed by condensation with tetrahydrofuranone (XIII) by means of DIEA in DMF gives the amide (XXVII). This compound is also deprotected with HCl as before and condensed with 5-methylisoxazol-3-ylcarbonyl chloride (XVIII) by means of pyridine to afford the protected compound (XXIX), which is finally treated with DDQ, yielding AG-7088.
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213. |
| 【2】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203. |
| 【3】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 32103 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 | |
| (XXVI) | 32105 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C25H36N2O7 | 详情 | 详情 | |
| (XXVII) | 32106 | ethyl (E,4S)-4-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C40H54FN3O9 | 详情 | 详情 | |
| (XXVIII) | 32107 | 5-methyl-3-isoxazolecarbonyl chloride | C5H4ClNO2 | 详情 | 详情 | |
| (XXIX) | 32108 | ethyl (E,4S)-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-4-[((2R,5S)-2-(4-fluorobenzyl)-6-methyl-5-[[(5-methyl-3-isoxazolyl)carbonyl]amino]-4-oxoheptanoyl)amino]-2-pentenoate | C40H49FN4O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The coupling of (X) with 5-methylisoxazole-3-carbonyl chloride (XI), yielded amide (XII). The alcohol group of (XII) was then oxidized to ketone (XIV) employing Dess-Martin periodinane (XIII). Finally, the 2,4-dimethoxybenzyl group (DMB) of (XIV) was cleaved by treatment with DDQ in hot acetonitrile.
| 【1】 Zhou, R.; Dragovich, P.S.; Webber, S.E.; et al.; Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C protease inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 45. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 36600 | (2S)-2-amino-N-[(1S)-2-[((1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-hydroxyethyl)amino]-1-(4-fluorobenzyl)-2-oxoethyl]-3-methylbutanamide | C37H44FN5O6S | 详情 | 详情 | |
| (XI) | 32107 | 5-methyl-3-isoxazolecarbonyl chloride | C5H4ClNO2 | 详情 | 详情 | |
| (XII) | 36601 | N-[(1S)-1-([[(1S)-2-[((1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-hydroxyethyl)amino]-1-(4-fluorobenzyl)-2-oxoethyl]amino]carbonyl)-2-methylpropyl]-5-methyl-3-isoxazolecarboxamide | C42H47FN6O8S | 详情 | 详情 | |
| (XIII) | 18845 | Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one | 87413-09-0 | C13H13IO8 | 详情 | 详情 |
| (XIV) | 36602 | N-[(1S)-1-([[(1S)-2-[((1S)-2-(1,3-benzothiazol-2-yl)-1-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2-oxoethyl)amino]-1-(4-fluorobenzyl)-2-oxoethyl]amino]carbonyl)-2-methylpropyl]-5-methyl-3-isoxazolecarboxamide | C42H45FN6O8S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Catalytic hydrogenation of 2-hydroxy-3-nitropyridine (I) in the presence of Pd/C affords 3-amino-2-hydroxypyridine (II). This is then acylated by 5-methylisoxazole-3-carbonyl chloride (III) to furnish the corresponding amide (IV). (1)
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; Johnson, T.O. Jr. (Agouron Pharmaceuticals, Inc.); Antipicornaviral cpds. and compsns., their pharmaceutical uses, and material for their synthesis. JP 2003515591; US 2001047006; US 6514997; WO 0140189 . |